Extra-pancreatic manifestations reported in association with pancreatitis; an international survey report

Background/objectives Local and systemic manifestations have been reported in association with pancreatitis, anecdotally. However, a systematic collection on the prevalence of each of these symptoms in pancreatitis is lacking. We aimed to determine the prevalence of symptoms and diagnoses reported by a cohort of patients with pancreatitis, refer to as “extra pancreatic manifestation of pancreatitis”. Methods Cross-sectional study approved by the IRB and administered through a REDCap survey by “Mission: Cure”, a nonprofit organization. Results Of the 225 respondents analyzed; 89% were adults, 69% females, 89% Caucasians with 74% residing in the USA. 42% of children and 50% of adults reported exocrine pancreatic insufficiency while 8% of children and 26% of adults reported DM. Type 3c DM was reported in all children and 45% of adult DM cases. Children were diagnosed with genetic or hereditary pancreatitis more frequently compared to adults (33.3% versus 8%; p = <0.001). Significantly more symptoms and diagnoses were reported by adults when compared to children including nighttime sweats, bloating, or cramping, greasy or oily stools, feeling cold and GERD with p values of 0.002, 0.006, 0.046, 0.002 and 0.003 respectively. Conclusions Adults with pancreatitis frequently report symptoms not known to be associated with pancreatitis. Studies investigating mechanisms for these associated symptoms should be explored.


Introduction
Although extra-pancreatic manifestations have long been reported in association with pancreatitis, there are gaps in literature on the prevalence of most of these diagnoses and symptoms associated with pancreatitis. Many of the reported manifestations are limited to case reports, case series, single center studies and few systematic reviews [1][2][3][4][5].
Other extra pancreatic manifestations that have been described in association with pancreatitis include panniculitis, polyarthritis (PPP) syndrome [13]. Cutaneous manifestations reported with pancreatitis include acanthosis nigricans, necrolytic migratory erythema, livedo reticularis and hemorrhagic skin lesions seen in severe acute pancreatitis (AP) [14]. Other symptoms that have been described with AP include fatigue [13], abdominal wall abscess and epididymoorchitis [15].
While extra-pancreatic manifestations in autoimmune (Ig4 related) pancreatitis have been described, and there are studies focusing on exocrine and endocrine insufficiency, data on the prevalence of extra pancreatic manifestations in AP and chronic pancreatitis (CP) are limited. Given the gaps in literature on the prevalence of some of these symptoms, the aim of this study is to systematically evaluate and compare the prevalence of extra-pancreatic manifestations reported by adults versus children with pancreatitis through an online questionnaire.

Methods
This is a cross-sectional anonymous survey approved by the Institutional Review Board at the University of Nebraska Medical Center (UNMC) as an exempt study: 0186-22-EX. The RED-Cap (Research Electronic Data Capture) administered anonymous survey used in this study was developed through several meetings by study investigators, C.D, M.A.H and personnel from Mission: Cure, including an adult patient with pancreatitis and the caregiver of a child with pancreatitis. The survey was launched via Mission: Cure email thread and social media from April 6 th to May 13 th , 2022. During this period (April 6 th to May 13 th , 2022), patients with pancreatitis and their caregivers who were part of the social support or network with Mission: Cure, were sent weekly reminders to complete the REDCap survey. Data from completed surveys was automatically available in REDCap for research purposes. Available data from completed surveys was assessed by research personnel for data analysis and further research purposes, 3 days after survey had closed to potential participants on May 16 th , 2022. Neither written nor oral consent was obtained since this was an anonymous survey administered via social media. However, we added a few sentences prior to survey questions indicating that completion of survey was voluntary, completion of survey indicated consent and children were not allowed to complete surveys, but their adult parents or legal guardians should complete survey on their behalf. The survey was administered and analyzed anonymously.
The survey was administered in English and divided into 4 sections: demographic, baseline clinical information, symptoms, and diagnoses. Our primary outcomes were extra pancreatic symptoms reported in adults versus children and our secondary outcomes were comparing known pancreatic symptoms reported in children versus adults.

Statistical analysis
Descriptive statistics (counts and percentages) were used to describe the cohort and by age groups (<18 years versus �18 years). Chi-square test or Fisher's exact test were used to compare groups for baseline characteristics, symptoms, and diagnoses between the two age groups. A 2-sided p value <0.05 was used to determine the significance of variables in all analyses. Data analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina).

Discussion
In this study we asked adults and children with pancreatitis about their experience with extra pancreatic symptoms and diagnosis. Almost all participants reported at least one extra pancreatic symptom (that is a symptom not commonly reported in pancreatitis) signifying the burden of the disease. The extra-pancreatic symptoms and diagnoses are present in most patients with pancreatitis and are more likely to occur in adults with pancreatitis than children.
To our knowledge, this is the first study to incorporate a patient reported perspective via an anonymously administered survey to determine the prevalence of extra-pancreatic manifestations in a cohort of patients with pancreatitis. Patients with pancreatitis often report other symptoms that have not been well-documented.
Have you experienced any of the symptoms noted below? (choice = None of these apply to me) Have you experienced any of these symptoms related to pancreatitis? (choice = None of the above symptoms apply to me)  Other organ-system involvement have been described with other diseases such as inflammatory bowel disease [16] and may parallel or precede intestinal activity. Reports in pancreatitis have been limited to case reports, case series, single center studies and a few systematic reviews [17][18][19][20]. A systematic review by Brown et al. revealed that a third of patients with acute pancreatitis will develop infectious complications with respiratory infection and bacteremia being the most common [17]. Another study by Kothari et al. [18] revealed an incidence of 34% of extra-pancreatic complications in adults admitted to the ICU with AP. These complications were associated with increased length of stay and the non-infectious complications increased mortality [18].
In our cohort, 90% of participants reported at least one extra-pancreatic symptom or diagnosis. This contrasts with the retrospective study by Abbasi et al. [21] where * 20% of patients (AA and Hispanic) in their cohort had extra-pancreatic manifestations. In that study, gastrointestinal (GI) bleed was the most common extra-pancreatic manifestation in about 22% of their patients. However, fatigue was the most common extra-pancreatic symptom in cohort and was reported by 79% of adults and 67% of children [21]. In this study, GI bleed was reported by about 11% of adults and no child reported a GI bleed. It is possible that the differences in symptom prevalence observed between our study and the retrospective study by Abbasi and colleagues may be due to the cohort differences in demographics (AA and Hispanic versus Caucasian) and diagnosis of pancreatitis (acute pancreatitis versus chronic pancreatitis) or even a reporting bias. Surprisingly, many participants reported symptoms associated with certain diseases surveyed, however, the percentage of reported diagnoses of these diseases were lower than the percentage of respondents reporting the symptoms associated with the diseases. This could represent an under-reporting of symptoms by these patients to their providers to necessitate further workup and proper diagnosis or missed opportunity by providers to make the diagnosis. We hope that these findings will prompt further studies in this area to determine the true prevalence of these diagnoses.
Although our study reveals important findings on the commonly reported symptoms in pancreatitis and extra pancreatic manifestations in a pancreatitis cohort, limitations still exist. Some of the limitations are in the sample size, the possible recall bias, possibility of gender bias as most subscribers to Mission: Cure mailing list identify as females and the lack of objective diagnosis by medical provider as a confirmation of those symptoms. Additionally, it is possible that symptoms reported may be related to other diagnoses not reported by these participants. However, the strengths of our study are in the inclusion of adult and children in the cohort  and focusing on the important aspects from the patient's point of view, as these may have been missed if this survey and study was driven by medical providers only. Lastly, the wide representation of a random international sample is an additional strength to the study that would allow for generalizability.

Conclusion
Patients with pancreatitis report extra-pancreatic symptoms with limited extra-pancreatic diagnoses. Improved awareness of these symptoms with subsequent diagnoses and treatment may reduce the frequency, severity of complications of pancreatitis and most importantly improve outcomes that are most impacting the patients with pancreatitis.
Supporting information S1 Checklist. STROBE statement-checklist of items that should be included in reports of observational studies. (DOCX)